Emerging Chimeric Antigen Receptor-Immune Cell Therapy for Pancreatic Cancer: Mechanisms, Clinical Advances, and Future Perspectives

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by a highly immunosuppressive tumor microenvironment (TME), dense stromal architecture, and limited response to conventional therapies. This review comprehensively examines the emerging role of chimeric antigen receptor (CAR)-engineered immune cells, including chimeric antigen receptor-T (CAR-T), CAR-macrophages (CAR-M), and CAR-natural killer (CAR-NK) cells, as innovative immunotherapeutic strategies for PDAC. We delve into the mechanistic foundations of these platforms, highlighting their unique abilities to target tumor-associated antigens, overcome stromal barriers, and remodel the immunosuppressive TME. Recent preclinical and clinical advances demonstrate promising antitumor activity, particularly with targets such as mesothelin, claudin18.2, and human epidermal growth factor 2 (HER2), though challenges related to antigen heterogeneity, TME suppression, and cell persistence remain. We further discuss synergistic approaches involving genetic engineering, microenvironment modulation, and combination therapies aimed at enhancing efficacy. Finally, we offer perspectives on the future direction of CAR-based therapies, including the development of next-generation constructs, allogeneic “off-the-shelf” products, and personalized combination regimens, underscoring their potential in pancreatic cancer.